tbuckley/cabot-search huggingface dataset:
EVALUATION OF PATIENT REPORTED TOXICITIES AND THE INFORMATION WE PROVIDE TO GLIOBLASTOMA PATIENTS
Authors: Sharon Fernandez, Florien Boele, Susan Short
Journal: Neuro-Oncology (2023)

Abstract AIMS To collect prospective, real- time data and lived experiences to determine if the chemo-radiotherapy pre- treatment information materials we provide to our patients need to be updated. METHOD A repeat cross-sectional, qualitative design was followed whereby individuals were interviewed at specific time points. These were defined as prior to radiotherapy (following planning scan and mould room); during radio- therapy (week 2) and post radiotherapy (4-6 weeks post radiotherapy). Patients and their caregivers were invited to participate in face-to-face, semi-structured interviews. Interviews were recorded, transcribed verbatim and thematically analysed. RESULTS Eighteen patients with confirmed diagnosis of glioblastoma and eleven caregivers consented for interview (n=9/n=5 prior to RT, n=5/n=4 during RT, n=4/n=2 post RT). Three main themes emerged. (1) Enhancing public awareness. Responses indicated that headway could be made in educating patients more effciently in terms of what chemo-radiotherapy related toxicities to expect. (2) Individual patient expectation. The majority of patients raised concern regarding insuffcient detail of chemo-radiotherapy related toxicities, with some patients expressing fear of the unexpected. (3) Impact of cancer treatment on daily life. Generally, patients and caregivers indicated that information booklets should provide clearer information on the impact of toxicities on patients’ and caregivers’ daily lives, at differing stages of treatment. CONCLUSIONS Patients and their caregivers provided constructive responses in relation to wanting more enhanced detail surrounding expected toxicities, toxicity severity and impact on daily life. All participants expressed wanting more information on the probability of likely toxicities to be experienced during and after chemo-radiotherapy, as current pre-treatment information given might be too generalised.
BIOPSY VS BEST SUPPORTIVE CARE IN GLIOBLASTOMA: IMPACT OF NO POST-OP RADIOTHERAPY ON OVERALL SURVIVAL
Authors: Siddarth Kannan, Isaac Phang
Journal: Neuro-Oncology (2023)

Abstract AIMS Best supportive care (BSC) is a management option generally considered glioblastoma patients with poor performance status, multiple co-morbidities or extensive disease. Navigated biopsy is recommended if there are multi- focal or multicentric disease. Patients are considered for biopsy based on performance score and co-morbidities with the aim of delivering post-operative radiotherapy. However, some patients are not offered radiotherapy. We examined patients who underwent biopsy and BSC to determine their overall outcomes METHOD Data from the neuro-oncology database and electronic patient records between 01/01/2018- 31/12/2022 were analyzed using GraphPad. RESULTS A total of 112 glioblastoma patients were included, 73 (median age: 65 years) patients underwent biopsy with 39 for best supportive care (median age: 80 years). The median overall survival for biopsy patients was 22.1 weeks (0.6-258) compared to 7.9 weeks (0.7-65.4) for BSC. 38 underwent post-operative radiotherapy. We further looked at biopsy patients that did not receive post-operation radiotherapy, 35 were identified and compared to BSC patients. There was a significant difference observed in overall survival between BSC (7.9 weeks) and No radiotherapy (14.7 weeks) groups (p&amp;lt;0.05). CONCLUSIONS We hypothesize that difference in overall survival between BSC and No radiotherapy patients could be due to 79.5% of BSC patients having significant co-morbidities compared to only 57% No radiotherapy patients. The group of BSC patients were also slightly older compared to patients that underwent biopsy. An interesting finding is that about 46% of BSC patients were not prescribed any dexamethasone compared to 11% of biopsy patients.
THE LINK BETWEEN M6A RNA METHYLATION AND R LOOPS IN PAEDIATRIC HIGH-GRADE GLIOMAS AND EPENDYMOMAS
Authors: Lauryn Walker, Masar Radhi, Helen Knight, Stuart Smith
Journal: Neuro-Oncology (2023)

Abstract AIMS Paediatric high-grade glioma (HGG) and ependymoma (EPN) are two devastating malignant tumours of the central nervous system that unfortunately carry a poor prognosis. As R loops are a known source of genomic instability in eukaryotic cells and have previously been revealed to undergo m6A RNA methylation, we sought to investigate the potential link between m6A methylation and R loops in relation to the pathogenesis of paediatric gliomas. METHOD Paediatric HGG cell lines including KNS42, GCE62 and SF188, and paediatric EPN cell lines including BXD- 1425EPN and EPN9, were utilised for experimental analysis, in addition to normal human astrocytes. Immuno- cytochemistry was performed to assess m6A and R loop levels in tumour cell lines compared to normal human astrocytes. Moreover, DNA damage levels and the effects of anti-cancer drugs on R loop levels were also examined. RESULTS Immunocytochemistry analysis revealed that overall m6A and R loop levels were higher in tumour cell lines compared to normal human astrocytes. Furthermore, differences in R loop levels were observed as a result of pharmacological and biological manipulation, including reduction in R loop abundance with PARP inhibitors. CONCLUSIONS The link between m6A methylation and R loops in relation to the pathogenesis of paediatric HGG and EPN is being investigated. The results of these experiments will be presented.
SHOULD CALCIUM SUPPLEMENTS BE PRESCRIBED PROPHYLACTICALLY FOR PATIENTS DIAGNOSED WITH A HIGH-GRADE GLIOMA (HGG) ON PROLONGED STEROID USE?
Authors: Jessica La, Victoria Hurwitz, Charlotte Robinson, Ellie Kostick, Aeron Suarez, Sarah Hedges, Nicola Harding, Renata Fukuthi, Lucy Brazil, Angela Swampillai, Omar Al-Salihi, Kazumi Chia, Vishal Manik, Ranjeev Bhangoo, Keyoumars Ashkan, Richard Gullan, Francesco Vergani, Jose Pedro Lavrador
Journal: Neuro-Oncology (2023)

Abstract AIMS The case study review will evaluate whether patients on long term steroid would benefit from calcium supplements and if a protocol for a bone density scan should be in place in relation to how long patients have been on steroids for. Duration of steroid use increases patients’ risk to steroid related toxicity when taken more than 3 weeks. These can include endocrine, skeletal and psychiatric side effects amongst many others. It is therefore important to assess how we can improve patients’ quality of life (QOL) with limited prognosis. METHOD In a single centre, patients diagnosed with a HGG will be reviewed if they were diagnosed with osteoporosis or spinal fractures between 2020- 2022, subsequent from prolonged steroid use. RESULTS All 7 patients identified had presented with severe lower back pain. 4 patients initially had bone density scans which prompted an MRI due to low minerals for patient age and osteoporosis, whilst the remaining 3 patients only had an MRI scan. All 7 patients had spinal fractures. The average dexamethasone use was 9 months unable to wean to stop. CONCLUSIONS Patients diagnosed with a HGG tumour sadly continue to have poor prognosis. For patients who have had limited debulking or biopsy only, this leaves them prone to require ongoing steroid use to help with side effects to improve QOL. Though the figures are small, we can see patients who struggled to wean to stop dexamethasone since their intracranial surgery have had their QOL impacted due to steroid toxicities with no previous related comorbidities.
SPATIAL TRANSCRIPTOMICS REVEALS TRANSLATIONAL AND INflAMMATORY CHANGES UPON ARGININE DEPRIVATION IN GLIOBLASTOMA
Authors: Jake Symington, Huan Huang, Tom Thorne, Kevin O’Neill, Elizabeth Want, Nelofer Syed
Journal: Neuro-Oncology (2023)

Abstract AIMS Glioblastoma is a primary brain malignancy with poor prognosis. The immunosuppressive microenvironment, molecular heterogeneity and the blood-brain barrier makes this tumour diffcult to treat. Targeted and immune therapies have shown limited success, highlighting the need for novel therapies. We previously demonstrated the effectiveness of arginine deprivation using ADI-PEG20 when combined with radiation. The aim of this study was to investigate transcriptomic changes initiated by ADI-PEG20 to potentiate the effects of radiation. METHOD To investigate this hypothesis, the CT2A syngeneic mouse model was used. To systemically deplete arginine, mice with brain tumours were treated with 5IU of ADI-PEG20 subcutaneously. Brains were harvested 6 days after treatment with ADI-PEG20 and analyzed by 10x Genomics Spatial Transcriptomics to investigate changes in the transcriptome. PartekFlow, GOFigure, PathfindR and EnrichR were used for bioinformatic analysis. RESULTS Arginine deprivation downregulated genes encoding ribosomal subunits. Gene Ontology and KEGG pathway analysis indicated an overall decrease in genes involved in transcription, translation and ribosomal biogenesis which were targets for the Myc transcription factor. Arginine Deprivation upregulated pro-inflammatory genes, including genes under the influence of IFN-y (GBPs and ISGs), indicating involvement of the STAT1 and NFkB transcription factors upon ADI-PEG20 administration. CONCLUSIONS Arginine deprivation reduced overall protein synthesis, conserving energy to favour translation and transcription of components of the pro-inflammatory immune response. Our study provides some insights into the mechanisms of action of ADI-PEG20 in enhancing the effects of standard of care for GBM.
NANO-OMICS FOR BLOOD BIOMARKER DISCOVERY IN GLIOBLASTOMA
Authors: Anita Liu, Marilena Hadjidemetriou, Thomas Kisby
Journal: Neuro-Oncology (2023)

Abstract AIMS Glioblastoma (GBM) remains one of the most aggressive cancers with an average survival of only 12-15 months. Current diagnostic methods are burdensome and ineffective, underscoring an urgent need to improve early detection and monitoring. The application of ‘liquid-biopsy’ markers holds great promises however, despite technological advances, to date there are no clinically used blood-based biomarkers for GBM. We have recently introduced the ‘Nano-Omics’ paradigm, which utilises nanoparticles (NPs) as scavenging platforms to capture and enrich disease-associated analytes from biological fluids for omics analyses. In this study, we utilised the Nano-Omics pipeline coupled with brain tissue mass spectrometry-based proteomics, to unveil GBM specific protein biomarker candidates. METHOD We exploited the spontaneous interaction of nanoparticles with blood proteins to comprehensively analyse the blood proteome of GL261 glioma-bearing C57BL/6J mice. Tumoural and peritumoural brain tissue originated from the same animals were also collected, micro-dissected and analysed by label free mass spectrometry in order to correlate the nanoparticle-enriched blood-circulating proteome with the tumour tissue proteome. RESULTS Our data revealed a number of GBM-specific biomarker candidates in blood even at low tumour burden, followed by validation in a human GBM clinical cohort. Furthermore, the peritumoural region of glioblastoma GBM displayed unique proteomic profiling, shedding light on the mechanism behind GBM infiltration and recurrence. CONCLUSIONS Our work highlights the importance of integrating blood and brain tissue proteomics and opens up new possibilities for further validation of the proteomic signatures discovered with the potential for further development of a much-needed blood test for GBM early detection and monitoring.
PREOPERATIVE BRAIN IRRADIATION IN GLIOBLASTOMA (POBIG TRIAL): FEASIBILITY AND EVALUATION OF TREATMENT RESPONSE IN ENHANCING AND NON-ENHANCING REGIONS
Authors: Mueez Waqar, Federico Roncaroli, Ibrahim Djoukhadar, Lisa Withington, Christopher Golby, Philip Whitehurst, Lauren Hewitt, Gabriella Forte, Claire O’leary, Rovel Colaco, Matthew Bailey, Konstantina Karabatsou, Pietro D’Urso, Catherine McBain, David Coope, Gerben Borst
Journal: Neuro-Oncology (2023)

Abstract AIMS Patients with glioblastoma have dismal outcomes and there is an urgent need for new treatment modalities. The POBIG trial is the first to evaluate the safety and feasibility of single-fraction preoperative radiotherapy for newly diagnosed glioblastoma. We report the results from our first dose arm. METHOD POBIG is a phase I radiotherapy dose and volume escalation trial. The first dose arm received 8Gy preoperative radiotherapy to a maximum irradiation volume of 30cm3. The irradiation field included enhancing and non- enhancing FLAIR hyperintense regions judged as highest risk for remaining as postoperative residuum. Part of the tumour remained unirradiated (&amp;lt;2Gy) with a margin for diagnostic sampling. Surgical resection took place within 1 week. Patients underwent diffusion/perfusion MRI scans before/after preoperative radiotherapy. RESULTS Two female and one male patient aged 61, 67 and 45 years, respectively, were enrolled. Preoperative radio- therapy was delivered at a dose of 8Gy to an irradiation volume of 7-30cm3. Near-total surgical resection was performed 2-3 days after preoperative radiotherapy treatment. Pathological examination of irradiated areas showed necrosis including fibrinoid necrosis of vessel walls. There was an increase in Ktrans permeability in both irradiated enhancing tumour (0.097,0.150) and unirradiated enhancing tumour (0.077,0.147) 24-hours after treatment. In contrast, no obvious changes were noted in irradiated (0.002,0.002) and unirradiated (0.002,0.004) non-enhancing FLAIR hyperintense regions or reference unirradiated contralateral white matter (0.000,0.000). CONCLUSIONS Preoperative radiotherapy is feasible in newly diagnosed glioblastoma. Very early radiotherapy changes manifest in enhancing tumour regardless of radiotherapy dose, evident as increased permeability and radiation- induced tumour necrosis.
ALTERNATIVE LENGTHENING OF TELOMERES (ALT) IS SEEN IN A PROPORTION OF OLIGODENDROGLIOMAS AND IT IS ASSOCIATED WITH A WORSE PROGNOSIS
Authors: Ho Keung Ng, Kay K K Li, Zhi-Feng Shi
Journal: Neuro-Oncology (2023)

Abstract AIMS Oligodendrogliomas are well known to be mutated for TERTp, which is enigmatically a diagnostic criteria for molecular glioblastoma by WHO2021. It is generally believed that gliomas that are TERTp negative maintain their telomere lengths by means of Alternative Lengthening of Telomeres (ALT) which is usually reflected by mutations of ATRX. Oligodendrogliomas are known to be non-mutated for ATRX unlike astrocytomas. TERT re-arrangement has also been shown to be an alternative way of TERT activation. METHOD We evaluated 112 oligodendrogliomas of both Grades 2 (n=87) and 3 (n=25) (all IDH-mutant, 1p19q co-deleted and 93% TERTp mutated by Sanger sequencing) by FISH for ALT, MYC, PDGFRA, EGFR , CDKN2A HD, and +7/-10, the latter events being associated with malignant transformation in low-grade gliomas. RESULTS 40 cases (35.7%) showed ALT and ALT positivity was associated with worse PFS (p=.024) and remained an in- dependent prognosticator in multivariate analysis. Amplification was found in MYC (6.3%), PDGFRA (10.7%), EGFR (0.8%), CDKN2A HD (6.25%) and +7/-10 (0%) and they had no prognostic significance, likely due to low occurrences. ALT was found to be associated with MYC amplification (p=.004). ALT-positive cases were further evaluated by FISH for TERT re-arrangement, and targeted panel DNA sequencing. CIC mutation (62.1%) was as- sociated with shorter OS in Grade 2 tumours (p=.023) and was the only significant finding from panel sequencing. TERT re-arrangement was only seen in 10.7% and had no prognostic significance. CONCLUSIONS ALT is seen in a proportion of oligodendrogliomas in spite of TERTp mutations and is associated with a worse prognosis.
MICROLENS - A DESIGN-CENTRED APPROACH TO AI IN HEALTHCARE
Authors: Lillie Pakzad-Shahabi, Radvile Mauricaite, Neuro-oncology PPI ICL_ICHT, Matthew Williams
Journal: Neuro-Oncology (2023)

Abstract AIMS MicroLens aims to co-develop tools and functions that enable patients &amp; caregivers to view and understand their own images. METHOD We used an explicit design-led approach, foregrounding user needs. Over 7 months we used a series of 4 meetings, written reports and online questionnaires capturing the views of 20 staff, patient and caregiver participants (55% patients &amp; caregivers; primary &amp; metastatic brain tumours) to explore feasibility and requirements for an AI-enhanced online medical image viewing tool. RESULTS There were two distinct patterns of preferred usage: smartphone-based “snapshot” approach vs. online plat- form with detailed review of all images. Participants wanted to use it as a “scan photo album” and said help in understanding the scans would be useful, but the desired level of technical performance was relatively low: patients and caregivers would mostly be happy with labelling of common simple structures and sides, rather than detailed annotation. Further benefits and concerns raised were ability to • share with family members who could not attend hospital appointments. • review their scans outside of an appointment. • better understand images. • Use tools to assist in the interpretation reducing staff workload • image-share causing more work for staff CONCLUSIONS Patients, caregivers and staff all expressed a clear view that an AI-enhanced online tool to allow patients to view and understand their images would be useful. However, there were significantly different use cases between different patients, and the level of functionality that patients &amp; caregivers expressed a need for was substantially simpler than that originally envisaged. We are currently implementing a prototype.
DIAGNOSTIC ACCURACY AND PROCESS EVALUATION WITH HEALTH ECONOMICS ANALYSIS OF AN ULTRA-FAST DIGITAL CONFOCAL MICROSCOPY SCANNER FOR REAL-TIME INTRA-OPERATIVE BRAIN TUMOUR DIAGNOSIS
Authors: William Bolton, Piravin Ramakrishnan, Dharsshini Reveendran, Vassili Crispi, Oluwaseyi Adebola, Rohit Sinha, Richard Digby, Aruna Chakrabarty, Ryan Mathew
Journal: Neuro-Oncology (2023)

Abstract AIMS Real-time intra-operative brain tumour tissue analysis in theatre can shorten turnaround times and facilitate repeated sampling; the latter can improve diagnostic accuracy and guide resection to maximise extent. We were the first team in the world to demonstrate the feasibility of an ultra-fast confocal microscopy scanner (Histolog®, SamanTree Medical SA) for real-time intra-operative brain tumour tissue diagnosis. The aim of this study is to demonstrate the diagnostic accuracy of Histolog® within a larger cohort of patients with brain tumours. METHOD An observational study with varying brain tumour types was conducted in a Tessa Jowell Brain Tumour Centre of Excellence. Adult patients undergoing brain biopsies or tumour debulking surgery were included. Multiple, freshly excised tissue samples were stained, and images captured within 60 seconds on Histolog® in the OR in parallel to current diagnostic pathways which included frozen section and smear cytology. Quantitative blinded concordance analysis between Histolog® images and gold standard histopathology was performed by a Consultant Neuropathologist. RESULTS A total of 50 cases are included in this analysis. This will include the quantitative analysis of n=50 cases and the concordance rating between Histolog® and gold standard traditional (frozen section and smear cytology) intra- operative histopathological diagnosis. The pilot data (n=12) that led to this larger study indicated a concordance rate of 83%. CONCLUSIONS Histolog® demonstrates non-inferior diagnostic accuracy when compared to current gold standard but significantly reduces the intra-operative time to achieve diagnosis. Future studies will investigate the effect of real- time margin zone analysis and explore machine learning for automatic computer aided diagnosis.
NON-CELL AUTONOMOUS INDUCTION OF A CANCER STEM CELL MOLECULAR PHENOTYPE IN AN IN VITRO MODEL OF SONIC HEDGEHOG MEDULLOBLASTOMA
Authors: Max van Essen, Sally Cowley, Esther Becker, Benjamin Schuster-Böckler, John Jacob
Journal: Neuro-Oncology (2023)

Abstract AIMS • Design a novel in vitro model of sonic hedgehog (SHH) medulloblastoma (SHH-MB) by co-culture of two distinct human SHH-MB cell lines with wild-type cerebellar organoids derived from human induced pluripotent stem cells. • Investigate how the phenotype of SHH-MB cells grown in co-culture differs from conventional monolayer or tumour spheroid cultures. METHOD DAOY and ONS76 cell lines were cultured as monolayers, tumour spheroids or co-cultured with wild type cerebellar organoids for twenty-five days. Cells were then processed for single cell RNA-seq yielding thousands of sequenced transcriptomes, which were analysed using the R package, Seurat and other software. RESULTS Tumour cells in co-culture could be distinguished from non-malignant cells by their distinct transcriptional profiles. Subpopulations of both cancer cell lines in co-culture upregulated neuronal differentiation genes. In co-culture only, a distinct subset of DAOY cells expressed multiple cancer stem cell markers including SOX2, OTX2, GLI2 and NES. The upregulation of SOX2 by these cells correlated with the co-expression of ERBB4, which encodes a tyrosine kinase receptor. CONCLUSIONS SHH-MB cells exhibited striking differences in their phenotype when grown under physiological conditions in co-culture. First, subpopulations of both types of cancer cells expressed a neuronal differentiation programme. Second, a cancer stem cell phenotype is revealed in TP53 mutant tumour cells that is centred on SOX2. Signalling by ERBB4 is a candidate in the upregulation of SOX2 in these cells and has previously been implicated in the pathogenesis of Group 4 medulloblastoma. Future experiments will test whether SOX2 and ERBB4 are co-expressed in patient tumour cells.
TRANSFORMING BRAIN CANCER TREATMENT, CARE AND RESEARCH: A CASE STUDY OF A SPECIALISED NATIONAL DIGITAL LEARNING AND NETWORKING PLATFORM FOR NHS HEALTH PROFESSIONALS
Authors: Nicky Huskens, Olivia Burton, Camille Goetz, Katie Bushby
Journal: Neuro-Oncology (2023)

Abstract AIMS The aim of this case study is to highlight the outcomes of a specialized digital learning platform, the Tessa Jowell Academy, to share excellence and jointly tackle challenges in brain cancer treatment, research and care. The free platform is co-designed with the professional community to address unmet needs and offers members features such as virtual courses, a clinical trial finder and a peer-to-peer learning service. METHOD Performance data has been collected over the last 12 months from: online member surveys and platform data (workshop registrations, member registrations, member logins, resource downloads, video views, certificate downloads, feature requests, clinical trial updates and national network sign-ups). RESULTS The platform has over 800 member registrations from 29 NHS hospitals from a range of disciplines. There have been: 42 peers matched through the platform, 19 clinical trials added, 4 national networks set-up and 35 workshops delivered to 1200 attendees live and on-demand. Common themes from member feedback include increased learning and networking opportunities, increased specialist support, improved confidence in MDT participation and increased knowledge of other sub-specialties. CONCLUSIONS It is well evidenced that specialized knowledge sharing between centres can contribute to better outcomes, improved patient satisfaction and access to research for rare diseases. This case study highlights the national demand and potential benefits of a specialized, national digital learning platform for NHS professionals working in brain cancer. As the platform grows, the impact will continue to be measured on a national level.